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Organ-specific sympathetic innervation defines visceral functions

Nature volume 637, pages 895–902 (2025)Cite this article

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Abstract

The autonomic nervous system orchestrates the functions of the brain and body through the sympathetic and parasympathetic pathways1. However, our understanding of the autonomic system, especially the sympathetic system, at the cellular and molecular levels is severely limited. Here we show topological representations of individual visceral organs in the major abdominal sympathetic ganglion complex. Using multi-modal transcriptomic analyses, we identified molecularly distinct sympathetic populations in the coeliac–superior mesenteric ganglia (CG–SMG). Of note, individual CG–SMG populations exhibit selective and mutually exclusive axonal projections to visceral organs, targeting either the gastrointestinal tract or secretory areas including the pancreas and bile tract. This combinatorial innervation pattern suggests functional segregation between different CG–SMG populations. Indeed, our neural perturbation experiments demonstrated that one class of neurons regulates gastrointestinal transit, and another class of neurons controls digestion and glucagon secretion independent of gut motility. These results reveal the molecularly diverse sympathetic system and suggest modular regulation of visceral organ functions by sympathetic populations.

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Fig. 1: Topographical representation of visceral organs in the CG–SMG sympathetic complex.
Fig. 2: Multi-transcriptomic analyses reveal molecularly and spatially distinct CG–SMG neural populations.
Fig. 3: Complementary organ projections by CG–SMGRXFP1 and CG–SMGSHOX2 neurons.
Fig. 4: Activation of CG–SMGRXFP1 neurons regulates secretory functions.
Fig. 5: Activation of CG–SMGSHOX2 neurons inhibits gut transit.

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Data availability

scRNA-seq data from CG–SMG cells are available at the Gene Expression Omnibus under the accession number GSE278457. The organ innervation and seqFISH data have been deposited at Zenodo (#13306861 and #13883320)59,60. Source data are provided with this paper.

Code availability

The code used in this paper is available at https://github.com/YTwTJ/Organ-Specific-Sympathetic-Innervation-Defines-Visceral-Functions.

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Acknowledgements

We thank the members of the Oka laboratory; Y. Zhang and T. Ichiki for helpful discussion and comments; J. Hauser, M. Oka and A. Tufenkjian for maintaining and genotyping mouse lines; Y. Zhang for helping with data analysis; Q. Liang and Y. Chen for providing the SHOX2–Cre line; B. Zhang and K. Frieda for help on seqFISH experiments; J. Linton, F. Horns and M. Elowitz for sharing the cell sorter; D. Anderson and the Single-Cell Profiling and Engineering Center for instrumental support with scRNA-seq experiments; and W. Han and I. De Araujo for advice on surgical techniques. This work was supported by Startup funds from the President and Provost of California Institute of Technology and the Biology and Biological Engineering Division of California Institute of Technology. Y.O. is also supported by the New York Stem Cell Foundation, the US National Institutes of Health (R01NS109997 and R01NS123918), the Alfred P. Sloan Foundation, the Edward Mallinckrodt Foundation and the Heritage Medical Research Institute.

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Authors and Affiliations

  1. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA

    Tongtong Wang, Bochuan Teng & Yuki Oka

  2. Andrew and Peggy Cherng Department of Medical Engineering, Division of Engineering and Applied Science, California Institute of Technology, Pasadena, CA, USA

    Dickson R. Yao & Wei Gao

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  1. Tongtong Wang
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  2. Bochuan Teng
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Contributions

T.W. and Y.O. conceived the research programme and designed the experiments. T.W. performed the transcriptomic, genetic, behavioural and anatomical experiments and analysed the data. B.T. performed the electrophysiological and behavioural experiments. D.R.Y. and W.G. designed and fabricated a microfluidic device for bile measurement. T.W. and Y.O. wrote the paper. Y.O. supervised the work.

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Correspondence to Yuki Oka.

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Extended data figures and tables

Extended Data Fig. 1 A computational pipeline for topographical mapping of visceral organs.

a, A schematic for building reference atlas through unsupervised alignment processing. b, Two reference images generated from DAPI-stained (top) or TH-stained (bottom) training images. c, Representative original image, auto-detected and registered WGA-positive cells (magenta) with DAPI staining background (blue or cyan) for eight organ sites as indicated (n = 8 mice per group). Scale bar, 500 μm.

Extended Data Fig. 2 WGA retrograde tracing quantifications.

a, Representative WGA-labeled cells (red) in the left and right nodose ganglia (NG) traced from the eight organ sites as indicated (n = 8 mice). b, c, Quantifications of WGA-positive cell number in the CG-SMG (b), left and right NG (c). d, Representative images and quantification of WGA-labeled cells in the left (top) and right (bottom) NG from dual-color organ tracing as indicated (n = 6 mice). Scale bar, 100 μm. Data are shown as mean ± s.e.m.

Source Data

Extended Data Fig. 3 Multi-transcriptomic analyses of CG-SMG cells.

a, ScRNA-seq analysis of CG-SMG cells. Left: UMAP embedding of CG-SMG major cell types (n = 24,873 cells). Vas. endo. cells, vascular endothelial cells. Middle and right: UMAP embedding of log-normalized Th (blue), Rxfp1 (red) and Shox2 (green) expression. b, Dot plot of cell-type-specific expression in CG-SMG major cell classes from seqFISH dataset. Dot size is proportional to the percentage of cells with transcript count >0 expression. Color scale represents normalized average gene expression. c, Heatmap of sympathetic neuronal marker gene expression in CG-SMG neurons. d, UMAP embedded seqFISH data from different CG-SMG areas with Harmony integration (n = 13,105 cells). e, Gene expression comparison between RXFP1+ and SHOX2+ neurons. f, Differentially expressed genes in RXFP1+ and SHOX2+ neurons are ranked by their expression fold change (log2). Rxfp1 and Shox2 rank the top 27th and 16th, respectively.

Extended Data Fig. 4 Transcriptomic and spatial analyses of SHOX2+ neuron subtypes.

a, Dot plot of differential gene expression in CG-SMGBMP3 and CG-SMGDSP neurons. b, Representative seqFISH images for the expression of Bmp3 (orange) and Dsp (cyan) in CG-SMG areas (top) and quantification of BMP3- and DSP-positive neurons (bottom, n = 5 sections of 3 mice per R-CG, SMG, L-CG). Scale bar, 100 μm. Data are presented as mean ± s.e.m.

Source Data

Extended Data Fig. 5 Two-color in situ hybridization for validating Cre expression of transgenic lines.

Representative images of Cre and endogenous gene expression in the CG and SMG samples of RXFP1-Cre, SHOX2-Cre, TH-Cre and wild-type (WT) animals as indicated. Nuclei were visualized with DAPI staining (blue). Data were quantified from more than two mice per group. DP, double-positive. n = 5, 5, 8, 3 slices for RXFP1-Cre CG, RXFP1-Cre SMG, WT CG, and WT SMG. n = 5, 10, 2, 3 slices for SHOX2-Cre CG, SHOX2-Cre SMG, WT CG, and WT SMG. n = 5, 4, 2, 3 slices for TH-Cre CG, TH-Cre SMG, WT CG, and WT SMG. Scale bar, 100 μm. All data are shown as mean ± s.e.m.

Source Data

Extended Data Fig. 6 Characterization Cre transgenic lines.

Representative images of Cre and endogenous gene expression in different ganglia and brain nuclei of RXFP1-Cre and SHOX2-Cre animals as indicated. Nuclei were visualized by DAPI staining (blue). Data were collected from more than two mice per group. NG, nodose ganglion; DRG, dorsal root ganglion (T12 or T13); SCG, superior cervical ganglion; SG, stellate ganglion; DMV, dorsal motor nucleus of the vagus; NA, nucleus ambiguous. Scale bar, 100 μm.

Extended Data Fig. 7 Histological verification for viral targeting.

a, Representative CG-SMG images for RXFP1-, SHOX2-, and TH-targeted neurons by AAV-FLEX-tdTomato with TH staining (blue). Scale bar, 500 μm. b, c, Histology (b) and quantification (c) for negative control of CG-SMG AAV injection. NG, nodose ganglion; DRG, dorsal root ganglion (T12 or T13); SCG, superior cervical ganglion; IMG, inferior mesenteric ganglion; DMV, dorsal motor nucleus of the vagus; NA, nucleus ambiguus; RVLM, rostral ventrolateral medulla. n = 6 RXFP1-Cre, 3 SHOX2-Cre, 6 TH-Cre mice for CG-SMG; 5 RXFP1-Cre, 3 SHOX2-Cre, 4 TH-Cre mice for NG. n = 3 animals per mouse line for the other sample groups. Scale bar, 100 μm. Data are presented as mean ± s.e.m.

Source Data

Extended Data Fig. 8 CG-SMG neural innervation of visceral organs.

a, Representative images for whole-mount organ innervation of CG-SMGRXFP1, CG-SMGSHOX2, CG-SMGTH neurons. Glucagon or alpha smooth muscle actin (aSMA) staining is indicated on the images. Magnified images for the pancreatic islet are from Fig. 3b. b, Representative images for the innervation of the myenteric plexus on the GI tract. The same set of animals were used as in Fig. 3b. c, Magnified images from Fig. 3b and Extended Data Fig. 9b for CG-SMG neural terminals in the myenteric and submucosal plexus along the GI tract. Nuclei were visualized by DAPI staining (blue). Scale bar, 100 μm.

Extended Data Fig. 9 Measurements of secretory processes.

a, A top-down view of the microfluidic device. b, A diagram of bile flow in the microfluidic chamber with tip stained by the black ink for automated fluid volume detection. c, Average bile flow rate before and after bile duct transection (BDx, n = 5 mice). d, Cholecystokinin (CCK) increased bile secretion (n = 5 mice). The dashed line is the linear regression fitted curve based on the initial 5 min of data. e,f, Quantified average bile flow rate after optogenetic activation of (e) CG-SMGRXFP1 or (f) CG-SMGTH neurons (n = 4, 6 for RXFP1-Cre;Ai32, and cagemate control mice, dataset from Fig. 4e; n = 4, 4 for TH-Cre;Ai32, and cagemate control mice). g, When bile was measured directly from the bile duct instead of the duodenum, bile production rate was unchanged, regardless of CG-SMGRXFP1 neuron activation (n = 4 mice). Light pulses of 2 ms at 20 Hz were applied at CG-SMG for 1 min as indicated by the blue shade. h, i, Representative histological images for optogenetic (h) and chemogenetic (i) experiments as indicated. Robust ChR2-EYFP (green) or Gq-mCherry (red) expression was confirmed with sympathetic neuron marker TH staining (blue). Scale bar, 100 μm. j, The control group from Fig. 4f is plotted. k, Vehicle administration had no effects on bile secretion (n = 2 mice). l, Application of labetalol hydrochloride, a norepinephrine receptor antagonist (Ant.), abolished the inhibition effects of CG-SMG neurons on bile secretion (n = 4 mice per group). m, Systemic glucose level under sated and 24-hour food-deprived (FD) states (n = 10 mice each). n, Effects of activating CG-SMGRXFP1 neurons on glucose homeostasis. Systemic glucose level was measured 20 min after intraperitoneal PBS (Veh) injection, as well as 20 min (CNO 20 m) or 40 min (CNO 40 m) after intraperitoneal CNO administration (n = 7 mice). o, Vehicle administration had no effects on glucagon release (n = 3 mice). p, Functional necessity of CG-SMG neurons on glucagon release to the hepatic portal vein. Neurons were ablated using AAV-FLEX-Caspase3 or AAV-FLEX-DTA. Compared to wild-type control, RXFP1-ablated animals exhibited significantly lower glucagon levels under fasting state. SHOX2-ablated animals had intact glucagon release. n = 13 mice for WT, 7 mice for RXFP1-Cre, 5 mice for SHOX2-Cre groups. q, Representative histological confirmation for ablation experiments with TH antibody staining (green). Arrows point to regions with ablated cells. Scale bar, 500 μm. *P < 0.05, **P < 0.01, ***P < 0.001 by two-tailed paired or unpaired Student’s t-test, or one-way ANOVA with Dunnett’s multiple comparisons test. Data are presented as mean ± s.e.m.

Source Data

Extended Data Fig. 10 Measurements of GI transit.

a, Quantification of colored food transit after different feeding durations as indicated (n = 5 mice per group). b, Chemogenetic activation of CG-SMGTH neurons increased food consumption within the initial 10-min feeding after deprivation (n = 12 mice). c, Vehicle administration had no effects on food transit (n = 6 mice for WT, and 4 mice for SHOX2-Gq groups). d, At 30-min time point, activating CG-SMGSHOX2 neurons significantly slower food transit compared to wild-type control animals (n = 5 mice per group). e, Inhibition effects of chemogenetic stimulation of CG-SMGTH neurons on stool expulsion. The number of stools after either intraperitoneal PBS (Veh) or CNO injection is plotted (left) and quantified (right, n = 7 mice). f, Spontaneous stool defecation of TH-Cre control animals with AAV-FLEX-tdTomato injection to CG-SMG (n = 6 mice). g, Chemogenetic stimulation of CG-SMGTH neurons significantly suppressed spontaneous stool expulsion, which was reversed by the application of labetalol hydrochloride (n = 8 mice). h, Chemogenetic activation of CG-SMGTH neurons significantly delayed the total GI transit (n = 6 mice). *P < 0.05, **P < 0.01, ***P < 0.001 by two-tailed paired Student’s t-test or one-way ANOVA with Dunnett’s multiple comparisons test. Data are presented as mean ± s.e.m.

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Wang, T., Teng, B., Yao, D.R. et al. Organ-specific sympathetic innervation defines visceral functions. Nature 637, 895–902 (2025). https://doi.org/10.1038/s41586-024-08269-0

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